Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis
Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis
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炎症诱导的S100A8激活Id3并促进结直肠肿瘤发生
DOI：
10.1002/ijc.29671
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发表时间：
2015-12-15
影响因子：
6.4
通讯作者：
Ma, Jian
中科院分区：
文献类型：
--
作者：
Zhang, Xuemei;Ai, Feiyan;Ma, Jian
S100A8和S100A9的异常表达与无法消退的炎症有关，并最终与癌症的发生有关，而允许炎症进展到特定癌症类型的潜在机制尚不清楚。在这里，我们报道了S100A8是由炎症诱导的，然后通过激活ID3(分化抑制因子3)促进了下游的结直肠癌的发生。利用基因表达谱和免疫组织化学方法，我们发现S100A8和S100A9在化学诱导的结肠炎相关癌小鼠模型和人类结直肠癌标本中均上调。此外，我们发现S100A8和S100A9通过募集巨噬细胞，促进结肠癌细胞的增殖和侵袭，以及在裸鼠模型中刺激最终加速肿瘤转移的循环而发挥趋化蛋白的作用。S100A8通过诱导ID3的表达同时抑制p21的表达来调节结肠癌细胞的周期和增殖。ID3的表达受Smad5的调控，Smad5由Akt1直接磷酸化。我们的研究揭示了一种新的机制，即炎症诱导的S100A8通过上游激活Akt1-Smad5-ID3轴来促进结直肠肿瘤的发生。有什么新的？目前尚不清楚为什么慢性炎症会发展为结肠炎相关癌症(CAC)。在本研究中，作者发现炎症因子S100A8通过Akt1-Smad5-ID3信号通路参与CAC的发生。ID3和其他ID蛋白是转录因子，在几种常见类型的癌症中，它们在血管生成、炎症、增殖和迁移中发挥重要作用。S100A8异常表达激活ID3的发现为炎症和癌症之间提供了一种新的联系。
The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically-induced colitis-associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation-induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1-Smad5-Id3 axis.What's new? It hasn't been clear why chronic inflammation may progress to colitis-associated cancers (CAC). In this study, the authors found that the inflammatory factor S100A8 contributes to CAC tumorigenesis through the Akt1-Smad5-Id3 signaling pathway. Id3 and other Id proteins are transcription factors that play an important role in angiogenesis, inflammation, proliferation, and migration in several common types of cancer. The finding that dysregulated S100A8 expression activates Id3 provides a novel link between inflammation and cancer.